scholarly journals Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity

2020 ◽  
Vol 21 (17) ◽  
pp. 5998
Author(s):  
Linda Feldbrügge ◽  
Katrin Splith ◽  
Ines Kämmerer ◽  
Sandra Richter ◽  
Anna Riddermann ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Wild Type ◽  
Protective Properties ◽  
Hepatic Expression ◽  
Markers Of Inflammation ◽  
Acute Necrotizing ◽  
Portal Fibroblast ◽  
Portal Fibroblasts

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.

scholarly journals Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice

2004 ◽  
Vol 286 (1) ◽  
pp. G60-G67 ◽  
Author(s):  
Yoshiya Ito ◽  
Edward R. Abril ◽  
Nancy W. Bethea ◽  
Robert S. McCuskey
Keyword(s):  
Nitric Oxide ◽  
Liver Injury ◽  
Cell Injury ◽  
Parenchymal Cell ◽  
Protective Role ◽  
Hepatic Expression ◽  
Inos Inhibitor ◽  
Microcirculatory Disturbances

Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l- N6-(1-iminoethyl)-lysine (l-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. l-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas l-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. l-NIL, but not l-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. l-NIL restored the sinusoidal perfusion, but l-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. l-NIL tended to minimize this infiltration, whereas l-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by l-NIL, whereas l-NAME further elevated it. l-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. l-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.

scholarly journals Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Zhengyu Jiang ◽  
Yan Meng ◽  
Lulong Bo ◽  
Changli Wang ◽  
Jinjun Bian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Great Part ◽  
Protective Role ◽  
Stress Indicators ◽  
Oxidative Reaction ◽  
Hepatic Expression ◽  
Jnk Cascade ◽  
Oxidative Stress Indicators

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H2O2, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia.

Roles of EXTL2, a member of the EXT family of tumour suppressors, in liver injury and regeneration processes

2013 ◽  
Vol 454 (1) ◽  
pp. 133-145 ◽  
Author(s):  
Satomi Nadanaka ◽  
Shoji Kagiyama ◽  
Hiroshi Kitagawa
Keyword(s):  
Liver Injury ◽  
Knockout Mice ◽  
Weight Ratio ◽  
Hepatocyte Proliferation ◽  
Chain Elongation ◽  
Wild Type ◽  
Ccl4 Administration ◽  
Ccl4 Treatment ◽  
Regeneration Processes

The gene products of two members of the EXT (exostosin) gene family, EXT1 and EXT2, function together as a polymerase in the biosynthesis of heparan sulfate. EXTL2 (EXT-like 2), one of the three EXTL genes in the human genome that are homologous to EXT1 and EXT2, encodes an N-acetylhexosaminyltransferase. We have demonstrated that EXTL2 terminates chain elongation of GAGs (glycosaminoglycans), and thereby regulates GAG biosynthesis. The abnormal GAG biosynthesis caused by loss of EXTL2 had no effect on normal development or normal adult homoeostasis. Therefore we examined the role of EXTL2 in CCl4 (carbon tetrachloride)-induced liver failure, a model of liver disease. On the fifth day after CCl4 administration, the liver/body weight ratio was significantly smaller for EXTL2-knockout mice than for wild-type mice. Consistent with this observation, hepatocyte proliferation following CCl4 treatment was lower in EXTL2-knockout mice than in wild-type mice. EXTL2-knockout mice experienced less HGF (hepatocyte growth factor)-mediated signalling than wild-type mice specifically because GAG synthesis was altered in these mutant mice. In addition, GAG synthesis in hepatic stellate cells was up-regulated during liver repair in EXTL2-knockout mice. Taken together, the results of the present study indicated that EXTL2-mediated regulation of GAG synthesis was important to the tissue regeneration processes that follow liver injury.

scholarly journals Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Beibei Zhang ◽  
Xiaoying Wu ◽  
Jing Li ◽  
An Ning ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cells ◽  
Normal Liver ◽  
Protective Role ◽  
Dependent Manner ◽  
Hepatic Progenitor Cells ◽  
Wild Type ◽  
Mice Model

Abstract Background Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown. Methods In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33−/− mice infected with S. japonicum. Results We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs’ expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33−/− mice with HPCs’ expansion. However, liver injury was more attenuated in IL-33−/− mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK. Conclusions Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.

scholarly journals Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jingyao Zhang ◽  
Sidong Song ◽  
Qing Pang ◽  
Ruiyao Zhang ◽  
Lei Zhou ◽  
...  
Keyword(s):  
Er Stress ◽  
Liver Toxicity ◽  
Hypoxia Inducible Factor ◽  
Pathological Process ◽  
Hepatocyte Proliferation ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Serotonin Deficiency ◽  
Apap Hepatotoxicity

Abstract Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH2-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

2006 ◽  
Vol 291 (3) ◽  
pp. G414-G423 ◽  
Author(s):  
Torsten Plösch ◽  
Jelske N. van der Veen ◽  
Rick Havinga ◽  
Nicolette C. A. Huijkman ◽  
Vincent W. Bloks ◽  
...  
Keyword(s):  
Total Sterol ◽  
Wild Type ◽  
Hepatic Expression ◽  
Maximal Stimulation ◽  
Functional Complex ◽  
Cholesterol Excretion ◽  
Excretion Rates ◽  
Cholesterol Secretion ◽  
Sterol Excretion

The ATP-binding cassette (ABC) half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates the secretion of plant sterols and cholesterol by hepatocytes into bile and their apical efflux from enterocytes. We addressed the putative rate-controlling role of Abcg5/Abcg8 in hepatobiliary cholesterol excretion in mice during (maximal) stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output rates were reduced by 82% and 35%, respectively, in chow-fed Abcg5−/− mice compared with wild-type mice. When mice were infused with the hydrophilic BS tauroursodeoxycholate, similar relative increases in bile flow, BS output, PL output, and total sterol output were observed in wild-type, Abcg5+/−, and Abcg5−/− mice. Maximal cholesterol and PL output rates in Abcg5−/− mice were only 15% and 69%, respectively, of wild-type values. An infusion of increasing amounts of the hydrophobic BS taurodeoxycholate increased cholesterol excretion by 3.0- and 2.4-fold in wild-type and Abcg5−/− mice but rapidly induced cholestasis in Abcg5−/− mice. Treatment with the liver X receptor (LXR) agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (fourfold), concomitant with the induction of Abcg5/ Abcg8 expression, but not in Abcg5−/− mice. In a separate study, mice were fed chow containing 1% (wt/wt) cholesterol. As expected, hepatic expression of Abcg5 and Abcg8 was strongly induced (fivefold and fourfold) in wild-type but not LXR-α-deficient ( Lxra−/−) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type mice and 2.0-fold in Lxra−/− mice, upon cholesterol feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, our data demonstrate that Abcg5/Abcg8 heterodimer-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.

scholarly journals Role of Non-coding RNA in Acetaminophen-induced Liver Injury

2021 ◽  
Author(s):  
Vivek Chowdhary ◽  
Pipasha Biswas ◽  
Kalpana Ghoshal
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Circular Rnas ◽  
Regulation Of Expression ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Regulatory Rnas

Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these non-coding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of ~25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (21-25 nucleotide) RNAs that are processed from precursor RNAs that have stem-loop structure, whereas non-coding RNAs >200 nucleotides are termed lncRNAs (long ncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP - induced liver injury (AILI).

scholarly journals Divergent Role of Gamma Interferon in a Murine Model of Pulmonary versus Systemic Klebsiella pneumoniae Infection

2002 ◽  
Vol 70 (11) ◽  
pp. 6310-6318 ◽  
Author(s):  
Thomas A. Moore ◽  
Michelle L. Perry ◽  
Andrew G. Getsoian ◽  
Michael W. Newstead ◽  
Theodore J. Standiford
Keyword(s):  
Liver Injury ◽  
Klebsiella Pneumoniae ◽  
Knockout Mice ◽  
Peripheral Blood ◽  
Pulmonary Infection ◽  
Wild Type ◽  
Gram Negative ◽  
Ifn Γ ◽  
Intravenous Inoculation

ABSTRACT Klebsiella pneumoniae is a leading cause of both community-acquired and nosocomial gram-negative-bacterial pneumonia. A further clinical complication of pulmonary K. pneumoniae infection is dissemination of bacteria from the lung into the peripheral blood, resulting in bacteremia concurrent with the localized pulmonary infection. Here, we report studies detailing the divergent role of gamma interferon (IFN-γ) in pulmonary versus systemic K. pneumoniae infection. Intratracheal inoculation of IFN-γ knockout mice resulted in significantly increased mortality compared to that observed for wild-type infected animals. Increased mortality correlated with a 100-fold increase in pulmonary bacteria within 2 days postinfection and upregulation of lung-associated interleukin-10 (IL-10) mRNA. Interestingly, IFN-γ knockout mice had a twofold reduction in plasma aminospartate transferase activity, indicating diminished liver injury following peripheral blood bacterial dissemination. To study the host response towards blood-borne bacteria in the absence of the ongoing pulmonary infection, intravenous inoculation studies were initiated. IFN-γ knockout mice were no more susceptible to intravenous infection than their wild-type counterparts. The consistent observation in IFN-γ knockout mice was for improved survival correlating with increased clearance of blood- and liver-associated bacteria. Intravenous inoculation resulted in a two- to threefold increase in hepatic IL-10 production 24 and 48 h postinfection. Liver injury was also significantly reduced in IFN-γ knockout mice. These data indicate that IFN-γ secretion is a critical mediator in the resolution of localized gram-negative pulmonary pneumonia. Surprisingly, host responses towards systemic infection with the same bacteria appear to be IFN-γ independent.

scholarly journals The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Hiroaki Fuji ◽  
Grant Miller ◽  
Takahiro Nishio ◽  
Yukinori Koyama ◽  
Kevin Lam ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Inflammatory Responses ◽  
Stellate Cells ◽  
Collagen Type I ◽  
Type I ◽  
Fibrotic Liver ◽  
Portal Fibroblasts

Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.

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